{"gene":"IL33","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2013,"finding":"Crystal structure of IL-33 in complex with the ectodomain of ST2 determined at 3.27 Å resolution. Structure-based mutagenesis and binding assays defined the molecular mechanism by which ST2 specifically recognizes IL-33, showing surface-charge complementarity is critical for ligand-binding specificity. Small-angle X-ray scattering revealed that ST2 possesses hinge flexibility between its D3 domain and D1D2 module, while IL-1RAcP is rigid in the unbound state. The solution architecture of the IL-33–ST2–IL-1RAcP ternary complex was also determined.","method":"X-ray crystallography, SAXS, structure-based mutagenesis, binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 3.27 Å combined with mutagenesis and SAXS in a single rigorous study","pmids":["23980170"],"is_preprint":false},{"year":2018,"finding":"Nuclear IL-33 binds chromatin with ~10-fold slower intranuclear mobility than IL-1α (measured by FRAP). Chromatin binding restricts IL-33 release upon necrosis (full-length IL-33 is more resistant to necrosis-induced release than truncated IL-33 lacking chromatin-binding activity). Upon release, IL-33 and histones form a high-molecular-weight complex that synergistically activates ST2-mediated signaling, indicating chromatin binding is a post-translational mechanism regulating IL-33 releasability and bioactivity.","method":"FRAP, overexpression in epithelial cells, necrosis-induced release assay, gel filtration/high-MW complex analysis, receptor signaling assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (FRAP, release kinetics, complex analysis, signaling) in a single rigorous study","pmids":["30108214"],"is_preprint":false},{"year":2014,"finding":"USP21, a ubiquitin-specific protease, interacts with IL-33 in the nucleus and deubiquitinates it, thereby maintaining IL-33 protein stability. Depletion of USP21 reduces IL-33 protein levels and diminishes IL-33-mediated NF-κB p65 promoter transcriptional activity, linking IL-33 ubiquitination to its nuclear function.","method":"Co-immunoprecipitation, overexpression/knockdown, proteasome assay, NF-κB reporter assay","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single Co-IP plus knockdown with functional readout, no structural validation","pmids":["25197364"],"is_preprint":false},{"year":2017,"finding":"IL-33 activates core stem cell genes (NANOG, NOTCH3, OCT3/4) in colon cancer cells via the ST2 signaling pathway and induces phosphorylation and activation of JNK; activated c-Jun then binds the promoters of these stem cell genes. IL-33 also recruits macrophages into the tumor microenvironment and stimulates them to produce prostaglandin E2, which further supports cancer stemness.","method":"In vitro stimulation, Western blotting for p-JNK, chromatin immunoprecipitation (c-Jun on stem cell gene promoters), overexpression/administration in vivo tumor models, macrophage co-culture","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating c-Jun binding plus in vivo and in vitro functional studies in a single lab","pmids":["28249897"],"is_preprint":false},{"year":2018,"finding":"IL-33 activates dendritic cells via an IL-33–ST2–MyD88–STAT1 signaling axis. MyD88 is required for IL-33-mediated increases in myeloid DC (mDC) number and upregulation of costimulatory molecules; ST2 and STAT1 cooperate with MyD88 to induce costimulatory molecule expression on mDCs in response to IL-33.","method":"In vivo rIL-33 administration, genetic knockout of MyD88/ST2/STAT1, flow cytometry, antigen cross-presentation assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic knockouts with defined cellular phenotype, single lab","pmids":["28011934"],"is_preprint":false},{"year":2018,"finding":"A loss-of-function splice-site mutation in IL33 (rs146597587-C) produces a truncated IL-33 protein that has normal intracellular localization but neither binds the IL-33 receptor ST2 nor activates ST2-expressing cells, demonstrating that the C-terminal region (last 66 amino acids) is required for receptor binding and functional activity.","method":"Whole-genome sequencing, allele-specific RNA sequencing, recombinant truncated IL-33 protein binding assay, cell activation assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding and activation assays on recombinant truncated protein, replicated in population and molecular experiments","pmids":["28273074"],"is_preprint":false},{"year":2019,"finding":"IL-33-deficient Treg cells show attenuated suppressive properties and facilitate tumor regression in an ST2-independent fashion. On activation, Il33-/- Treg cells exhibit epigenetic reprogramming with increased chromatin accessibility at the Ifng locus, leading to elevated IFN-γ production via an NF-κB–T-bet-dependent mechanism. IFN-γ ablation restores Il33-/- Treg cell suppressive properties, establishing IFN-γ as the effector of IL-33-dependent Treg stability.","method":"Genetic knockout (Il33-/- Tregs), ATAC-seq, in vivo tumor models, IFN-γ ablation rescue experiment","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ATAC-seq, genetic KO, epistasis rescue with IFN-γ ablation) in a single rigorous study","pmids":["31844326"],"is_preprint":false},{"year":2020,"finding":"Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in hippocampal CA1. Neuronal activity blockade increases IL-33 expression and secretion by CA1 astrocytes; this IL-33 stimulates excitatory synapse formation and neurotransmission by activating the neuronal IL-33 receptor complex and promoting synaptic recruitment of PSD-95. Conditional knockout of IL-33 in CA1 astrocytes decreases excitatory synapse number, and blockade of IL-33/ST2 signaling impairs homeostatic plasticity and spatial memory.","method":"Conditional KO, optogenetic inhibition, tetrodotoxin slice experiments, in vivo rIL-33 administration, intracerebroventricular decoy receptor injection, behavioral memory assays, immunostaining for PSD-95","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KO, optogenetics, pharmacological blockade, behavioral assays) in a single rigorous study","pmids":["33443211"],"is_preprint":false},{"year":2022,"finding":"IL-33 promotes microglial synapse remodeling during brain development. Supraphysiological IL-33 alters the microglial enhancer landscape and increases binding of AP-1/FOS transcription factors, inducing expression of the scavenger receptor MARCO. CNS-specific deletion of IL-33 leads to increased excitatory/inhibitory synaptic balance and absence-like epileptiform activity; MARCO-deficient mice recapitulate excess thalamic excitatory synapses, indicating MARCO as a downstream mediator of IL-33-driven synapse engulfment.","method":"CNS-specific IL-33 KO mice, ATAC-seq/enhancer landscape analysis, MARCO KO, single-cell electrophysiology, EEG, synapse counting","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with epigenomic profiling and functional electrophysiological readouts in a single rigorous study","pmids":["36520518"],"is_preprint":false},{"year":2024,"finding":"Oxidized IL-33 (IL-33ox), a non-ST2-binding form, activates an ST2-independent pathway by forming a complex with RAGE and EGFR on airway epithelial cells. Activation of this RAGE/EGFR complex impairs epithelial wound closure and induces airway remodeling (increased mucus-producing cells, reduced epithelial defense functions) in vitro and in COPD ALI cultures.","method":"In vitro epithelial damage assays, 3D air-liquid interface models, bulk and single-cell RNA sequencing, antibody-based pathway neutralization","journal":"The European respiratory journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex formation and functional consequences demonstrated in multiple in vitro models, single lab","pmids":["37442582"],"is_preprint":false},{"year":2022,"finding":"Thrombin directly cleaves IL-33 at specific amino acid residues (R48 and R106) to generate a mature, biologically active form with potent ST2-stimulating activity. Low-molecular-weight heparin (indirect thrombin inhibitor) restrains papain- and fungus-induced type 2 immune responses by inhibiting IL-33 cleavage in vivo.","method":"In vitro cleavage assay (identification of cleavage sites R48/R106), in vivo mouse models with thrombin inhibitors, ELISA, ILC2 functional assays","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage assay with site identification plus in vivo rescue, single lab","pmids":["34995358"],"is_preprint":false},{"year":2023,"finding":"MDM2 (an E3 ubiquitin ligase) ubiquitinates the N-terminus of IL-33 and sustains its stability in epithelial cells. PLP (active form of vitamin B6) reduces MDM2-mediated IL-33 polyubiquitination and decreases IL-33 levels through the proteasome pathway, thereby dampening type 2 immune responses.","method":"In vivo PLP/PL administration, Pdxk heterozygous mice, ubiquitination assay, proteasome inhibitor experiments, co-immunoprecipitation","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay identifying MDM2 as the E3 ligase combined with genetic and pharmacological in vivo evidence, single lab","pmids":["37217797"],"is_preprint":false},{"year":2021,"finding":"Focal adhesion kinase (FAK) controls chromatin accessibility at the Il33 gene promoter/enhancer regions. FAK kinase activity is required for c-Jun (AP-1) binding to the Il33 enhancer, thereby regulating IL-33 gene expression. ATAC-seq integrated with RNA-seq demonstrated FAK-dependent chromatin accessibility linked to Il33 differential expression.","method":"ATAC-seq, RNA-seq, ChIP (c-Jun binding to Il33 enhancer), pharmacological/genetic FAK manipulation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ATAC-seq and ChIP with FAK-dependent c-Jun binding to IL33 enhancer, single lab","pmids":["33420223"],"is_preprint":false},{"year":2021,"finding":"Sprouty2 loss in colonic epithelial cells activates PI3K/Akt signaling leading to GSK3β inhibition, which in turn drives epithelial IL-33 expression. Elevated epithelial IL-33 increases stromal IL-13+ cells in vivo; IL-13 then induces tuft and goblet cell expansion. This PI3K–Akt–GSK3β–IL-33–IL-13 axis links epithelial signaling to secretory cell differentiation.","method":"Conditional Sprouty2 KO, in vivo intestinal phenotyping, in vitro organoids with PI3K/Akt inhibitors, GSK3β inhibitor treatment, IL-13 neutralization","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO combined with pharmacological epistasis and organoid experiments in a single lab","pmids":["33547321"],"is_preprint":false},{"year":2022,"finding":"IL11 stimulation of fibroblasts induces IL-33 expression (38-fold upregulation) in a STAT3-dependent (not MEK/ERK-dependent) manner, as demonstrated by pharmacological inhibition of STAT3 versus MEK/ERK. IL11 also upregulates IL1RL1 (the IL-33 receptor) 18-fold in the same cells, priming the IL-33 alarmin response.","method":"Primary human fibroblast culture, RNA sequencing, STAT3 and MEK/ERK pharmacological inhibitors, proteomics","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq and pathway inhibitors identifying STAT3 as the required signaling node, single lab","pmids":["36012165"],"is_preprint":false},{"year":2019,"finding":"IL-33 activates mTORC1 in CD8+ T cells (evidenced by increased phospho-S6 ribosomal protein), leading to upregulation of Glut1 and glycolytic enzymes via mTORC1, and increased glucose uptake and lactate production (Warburg effect). mTORC1 inhibitors suppressed IL-33-induced CD8+ T cell activation. Extracellular (not nuclear) IL-33 contributed to CD8+ T cell activation in LCMV infection in vivo.","method":"Adoptive transfer of IL-33 KO vs. WT T cells, in vitro stimulation assays, phospho-S6 Western blot/flow cytometry, mTORC1 inhibitor treatment, glycolytic rate assay, glucose uptake measurement","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoprotein assays, pharmacological inhibition, and metabolic assays in a single lab","pmids":["34411293"],"is_preprint":false},{"year":2011,"finding":"IL-33 promotes acute kidney injury (AKI) through CD4+ T cell-mediated production of CXCL1. Administration of soluble ST2 (decoy receptor) reduced CD4+ T cell infiltration, serum creatinine, ATN and apoptosis; conversely, recombinant IL-33 exacerbated AKI, and this exacerbation did not occur in CD4-deficient mice. CXCL1 receptor-deficient mice also showed attenuated AKI, placing the pathway as IL-33 → CD4 T cells → CXCL1 → renal injury.","method":"Soluble ST2 administration, recombinant IL-33 administration, CD4-deficient mice, CXCL1 receptor KO mice, serum creatinine, histopathology, cytokine ELISA","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis across multiple KO/deficient mouse strains with defined cellular phenotype, single lab","pmids":["21949094"],"is_preprint":false},{"year":2010,"finding":"IL-33 exacerbates autoantibody-induced arthritis specifically through mast cells expressing ST2. Mast cell-deficient mice and ST2-/- mice failed to show IL-33-mediated disease exacerbation; reconstitution of ST2-/- recipients with WT mast cells (but not ST2-/- mast cells) restored IL-33-mediated exacerbation. IL-33 enhanced autoantibody-mediated mast cell degranulation in vitro and in synovial tissue in vivo.","method":"ST2-/- mice, mast cell-deficient mice, mast cell reconstitution experiments, in vitro mast cell degranulation assay, in vivo synovial tissue analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal reconstitution experiments with WT and ST2-/- mast cells, plus in vitro and in vivo validation","pmids":["20139274"],"is_preprint":false},{"year":2024,"finding":"Active secretion of IL-33 from astrocytes occurs via an unconventional protein secretion pathway dependent on interaction with TMED10 (transmembrane emp24 domain 10). The IL-1-like cytokine domain of IL-33 mediates this interaction. IFN-γ promotes active secretion. Knockout of Il-33 or its receptor St2 induced hippocampal and spinal cord astrocyte activation and depressive-like behavior in naïve mice.","method":"Co-immunoprecipitation (IL-33 with TMED10), domain mapping, IL-33/ST2 conditional KO, behavioral assays, EAE model","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus multiple KO phenotypes, single lab","pmids":["38663774"],"is_preprint":false},{"year":2014,"finding":"Epithelial nuclear IL-33 is upstream of IL-8 and IL-6 production in esophageal epithelial cells. IFN-γ induces nuclear IL-33 expression via a JAK/p38 MAPK/STAT1 pathway; IL-33 knockdown (siRNA) dampens IFN-γ- and deoxycholic acid-induced IL-8 and IL-6 production, establishing a non-cytokine, intranuclear regulatory function for IL-33 in esophageal inflammation.","method":"IL-33 siRNA knockdown, STAT1 siRNA, JAK and p38 MAPK inhibitors, cytokine ELISA, stratified epithelial culture model","journal":"Journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with pharmacological pathway dissection in an organotypic model, single lab","pmids":["25129514"],"is_preprint":false},{"year":2021,"finding":"The asthma-associated SNP rs1888909 within an enhancer-blocking element at the IL33 locus is associated with IL33 gene expression in airway epithelial cells and IL-33 protein levels in plasma, potentially through differential binding of the transcription factor OCT-1 (POU2F1) to the risk allele. Chromatin conformation capture showed this 5 kb region loops to the IL33 promoter.","method":"3C (chromatin conformation capture), reporter assays (enhancer-blocking), eQTL analysis in airway epithelial cells, OCT-1 binding assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin looping (3C) and reporter assays with OCT-1 binding, single lab","pmids":["34675193"],"is_preprint":false},{"year":2019,"finding":"Glutaredoxin-1 (Glrx) controls IL-33 production in macrophages by regulating de-glutathionylation of TRAF6, which is required for TRAF6 activation; this in turn activates IKKβ and NF-κB, which drives IL-33 transcription as a NF-κB-responsive gene. Glrx knockdown also impairs downstream IL-33-induced (exogenous, via ST2L) IL-33 mRNA induction.","method":"Glrx KO mice, siRNA knockdown in RAW264.7 cells, chromatin IP-seq (NF-κB binding at IL-33 promoter), TRAF6 glutathionylation assay, NF-κB inhibitors","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq for NF-κB, TRAF6 glutathionylation assay, genetic KO, single lab","pmids":["30682073"],"is_preprint":false},{"year":2018,"finding":"IL-33 expression in Multiple Sclerosis PBMCs is regulated by HDAC3: IL-33 expression is inhibited by the HDAC inhibitor Trichostatin A (TSA), while IL-1β expression is not, indicating specific epigenetic regulation of IL-33 by HDAC activity. LPS stimulation co-induces IL-33 and HDAC3 in RRMS patients.","method":"HDAC inhibitor (TSA) treatment of PBMCs, LPS stimulation, RT-PCR/protein quantification","journal":"Annals of clinical and translational neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pharmacological inhibitor experiment without ChIP or direct HDAC3-IL33 interaction evidence, single lab","pmids":["25215310"],"is_preprint":false},{"year":2023,"finding":"P2Y13 receptor (a purinergic GPCR) acts as a gatekeeper of nuclear IL-33 release in airway epithelial cells. Aeroallergen or virus exposure induces extracellular ADP/ATP release, activating P2Y13-R, which drives nuclear-to-cytoplasmic translocation and subsequent extracellular release of IL-33. Genetic deletion or pharmacological antagonism of P2Y13-R ablates IL-33 translocation and release in response to allergens and rhinovirus.","method":"P2Y13-R knockout mice and pharmacological antagonists, allergen/virus exposure of primary AECs, immunohistochemistry for IL-33 localization, ELISA","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO combined with pharmacological antagonism and direct localization measurements, single lab","pmids":["34860143"],"is_preprint":false},{"year":2020,"finding":"S. aureus second immunoglobulin-binding protein (Sbi) directly drives rapid IL-33 release from human keratinocytes independently of the Toll-like receptor pathway. Sbi was identified by FPLC fractionation and mass spectrometry, confirmed by recombinant expression and S. aureus Sbi mutant strains; IL-33 was essential for the in vivo immune response to S. aureus in eczema-prone mice.","method":"FPLC fractionation, mass spectrometry, recombinant Sbi expression, Sbi mutant bacteria, ex vivo skin explants, IL-33 KO mice","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification of Sbi, confirmed with recombinant protein and loss-of-function bacterial mutant, in vivo validation, single lab","pmids":["33011245"],"is_preprint":false},{"year":2024,"finding":"Lenvatinib increases NDUFA4L2 expression in HCC cells, which promotes IL-33 production and secretion. Secreted IL-33 triggers neutrophil extracellular trap (NET) formation by increasing PADI4 expression in neutrophils via the Akt/mTOR signaling pathway. IL-33 knockdown in HCC cells reduced NET formation in the tumor microenvironment.","method":"IL-33 KO/knockdown in tumor cells, NDUFA4L2 overexpression, mTOR inhibitor (rapamycin), PADI4 inhibitor (GSK484), NET quantification (CitH3, MPO-DNA), in vivo HCC mouse models","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and pharmacological epistasis with multiple functional readouts, single lab","pmids":["39585643"],"is_preprint":false},{"year":2015,"finding":"IL-33 stimulation induces ICAM-1 expression on murine bone-marrow-derived mast cells at both mRNA and protein levels. This induction is dependent on NF-κB signaling: pre-treatment with an NF-κB inhibitor dramatically reduces ICAM-1 expression. IL-33-treated mast cells show increased cell adhesion to LFA-1-coated surfaces.","method":"BMMCs stimulation, siRNA knockdown of ICAM-1, NF-κB inhibitor, cell adhesion assay, in vivo intradermal IL-33 injection with histological analysis","journal":"Allergology international : official journal of the Japanese Society of Allergology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibitor combined with siRNA and in vivo validation, single lab","pmids":["26666474"],"is_preprint":false},{"year":2018,"finding":"IL-33 facilitates colorectal cancer cell proliferation via ST2 receptor → NF-κB signaling → COX2 upregulation → PGE2 production. ST2 blockade, NF-κB inhibition (shP65), and COX2 selective inhibitor or PGE2 neutralizing antibody each abolished the IL-33 proliferation-promoting effect. ST2-negative sorted primary CRC cells did not respond to IL-33.","method":"ST2 blocking antibody, flow cytometry sorting of ST2+/- cells, NF-κB shRNA, COX2 inhibitor, PGE2 neutralizing antibody, colony formation and viability assays, in vivo IL-33 transgenic tumor growth","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitors and genetic tools placing IL-33 in a defined signaling pathway, single lab","pmids":["30119635"],"is_preprint":false}],"current_model":"IL-33 is a dual-function nuclear alarmin cytokine that resides in the nucleus bound to chromatin (slowing its release upon necrosis), is actively secreted via an unconventional TMED10-dependent pathway in astrocytes, and—once in the extracellular space—binds its primary receptor ST2 (with IL-1RAcP as co-receptor, whose ternary complex structure is solved) to activate downstream MyD88–NF-κB, MAPK, and mTORC1–glycolytic signaling cascades in diverse immune and non-immune cells; its bioactivity is regulated post-translationally by ubiquitination (MDM2 as E3 ligase, USP21 as deubiquitinase), protease cleavage (thrombin at R48/R106 generates a mature form), oxidation (IL-33ox loses ST2 binding but engages a RAGE/EGFR complex), and epigenetic control of its transcription by FAK-dependent c-Jun/AP-1 chromatin accessibility and NF-κB via TRAF6/Glrx redox signaling."},"narrative":{"mechanistic_narrative":"IL-33 is a dual-function nuclear alarmin cytokine that links cellular damage and tissue-resident signaling to inflammatory, immune, and neural programs by acting both as a chromatin-associated nuclear factor and as a secreted ligand for the receptor ST2 [PMID:23980170, PMID:30108214, PMID:25129514]. In the nucleus IL-33 binds chromatin with markedly slower mobility than IL-1α, a property that restrains its release upon necrosis and that, upon release, generates high-molecular-weight IL-33–histone complexes which synergistically activate ST2 signaling [PMID:30108214]; nuclear IL-33 also functions cell-intrinsically, sitting upstream of IL-8/IL-6 production in epithelial cells and stabilizing the suppressive phenotype of regulatory T cells, where its loss reprograms chromatin accessibility at the Ifng locus to drive NF-κB–T-bet–dependent IFN-γ [PMID:25129514, PMID:31844326]. Extracellularly, IL-33 engages ST2 with IL-1RAcP as co-receptor; the ternary complex architecture and the surface-charge complementarity governing ST2 recognition have been defined structurally, and the C-terminal IL-1-like domain is required for receptor binding and activity [PMID:23980170, PMID:28273074]. ST2 engagement activates MyD88-dependent NF-κB, MAPK/JNK, STAT1, and mTORC1–glycolytic cascades across diverse cells—dendritic cells, mast cells, CD8+ T cells, and tumor epithelium—driving costimulatory molecule expression, mast cell degranulation, glycolytic activation, and NF-κB–COX2–PGE2–dependent proliferation and cancer stemness [PMID:28011934, PMID:20139274, PMID:34411293, PMID:30119635, PMID:28249897]. Release and bioactivity are tightly regulated post-translationally: thrombin cleaves IL-33 at R48/R106 to generate a potent mature form, oxidation produces a non-ST2-binding IL-33ox that instead signals through a RAGE/EGFR complex, and protein stability is set by competing MDM2-mediated ubiquitination and USP21-mediated deubiquitination [PMID:34995358, PMID:37442582, PMID:37217797, PMID:25197364]. IL33 transcription and release are themselves controlled by FAK-dependent c-Jun/AP-1 chromatin accessibility, TRAF6/Glrx redox-driven NF-κB signaling, purinergic P2Y13 gating, and unconventional TMED10-dependent secretion from astrocytes, where IL-33 governs synaptic plasticity and microglial synapse remodeling [PMID:33420223, PMID:30682073, PMID:34860143, PMID:38663774, PMID:33443211, PMID:36520518].","teleology":[{"year":2013,"claim":"Established the structural basis by which IL-33 is recognized by its receptor, answering how ligand specificity and ternary signaling-complex assembly are achieved.","evidence":"X-ray crystallography, SAXS and structure-based mutagenesis of the IL-33–ST2 and IL-33–ST2–IL-1RAcP complexes","pmids":["23980170"],"confidence":"High","gaps":["Does not address how oxidation or proteolysis alters the receptor interface","No structure of the chromatin-bound nuclear form"]},{"year":2018,"claim":"Resolved why full-length IL-33 is retained intracellularly, showing chromatin binding is a post-translational brake on release that also produces signaling-active IL-33–histone complexes.","evidence":"FRAP, necrosis-induced release assays and high-MW complex analysis in epithelial cells","pmids":["30108214"],"confidence":"High","gaps":["Chromatin-binding domain and target loci not mapped","In vivo relevance of IL-33–histone complexes not established"]},{"year":2017,"claim":"Connected the C-terminal region of IL-33 directly to receptor function through a natural loss-of-function variant.","evidence":"Whole-genome sequencing plus recombinant truncated-protein binding and activation assays","pmids":["28273074"],"confidence":"High","gaps":["Does not address nuclear functions of the truncated protein beyond localization"]},{"year":2010,"claim":"Defined a cell-type-specific effector mechanism, showing IL-33 exacerbates arthritis specifically via ST2-expressing mast cells.","evidence":"ST2-/- and mast-cell-deficient mice with reciprocal WT vs ST2-/- mast cell reconstitution","pmids":["20139274"],"confidence":"High","gaps":["Downstream signaling within mast cells not dissected here"]},{"year":2011,"claim":"Placed IL-33 in a defined organ-injury cascade, showing it drives acute kidney injury through CD4 T-cell-derived CXCL1.","evidence":"Soluble ST2 decoy, recombinant IL-33, and CD4-deficient and CXCL1-receptor-KO mice","pmids":["21949094"],"confidence":"Medium","gaps":["Direct receptor target cell not pinpointed","Single lab"]},{"year":2014,"claim":"Identified opposing enzymatic control of IL-33 stability, establishing USP21 as a nuclear deubiquitinase that preserves IL-33 and its NF-κB-promoting activity.","evidence":"Co-IP, knockdown, proteasome and NF-κB reporter assays","pmids":["25197364"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Ubiquitin linkage type and E3 partner not defined here"]},{"year":2014,"claim":"Demonstrated a non-cytokine intranuclear function, with IFN-γ-induced nuclear IL-33 acting upstream of IL-8/IL-6 in epithelial inflammation.","evidence":"siRNA knockdown with JAK/p38/STAT1 pathway inhibitors in organotypic esophageal culture","pmids":["25129514"],"confidence":"Medium","gaps":["Molecular mechanism of nuclear gene regulation not defined","Single lab"]},{"year":2018,"claim":"Mapped the receptor-proximal signaling required for IL-33-driven dendritic cell activation.","evidence":"In vivo rIL-33 with MyD88, ST2 and STAT1 knockouts and flow cytometry","pmids":["28011934"],"confidence":"Medium","gaps":["Does not separate direct vs indirect effects on DCs"]},{"year":2017,"claim":"Linked ST2 signaling to transcriptional reprogramming, showing IL-33 drives cancer stemness via JNK/c-Jun activation of stem-cell genes.","evidence":"Western blot, ChIP for c-Jun on stem-cell promoters, in vivo tumor and macrophage co-culture models","pmids":["28249897"],"confidence":"Medium","gaps":["Direct c-Jun-to-stemness causality not isolated from microenvironment effects"]},{"year":2018,"claim":"Defined a clinically actionable epigenetic regulator of IL-33, showing HDAC3-dependent expression in MS PBMCs.","evidence":"HDAC inhibitor treatment of PBMCs with RT-PCR readout","pmids":["25215310"],"confidence":"Low","gaps":["Single pharmacological inhibitor without ChIP or direct HDAC3-IL33 interaction evidence","Specificity over other HDACs untested"]},{"year":2019,"claim":"Revealed a receptor-independent nuclear role of IL-33 in restraining Treg-derived IFN-γ via chromatin accessibility at the Ifng locus.","evidence":"Il33-/- Treg ATAC-seq, in vivo tumor models and IFN-γ ablation rescue","pmids":["31844326"],"confidence":"High","gaps":["Mechanism by which nuclear IL-33 alters Ifng chromatin not defined"]},{"year":2019,"claim":"Connected IL-33 to metabolic rewiring, showing extracellular IL-33 drives mTORC1-dependent glycolysis in CD8+ T cells.","evidence":"Phospho-S6 assays, mTORC1 inhibitors and glycolytic/glucose-uptake measurements with IL-33 KO T cells","pmids":["34411293"],"confidence":"Medium","gaps":["Direct ST2 dependence of the metabolic effect not isolated"]},{"year":2019,"claim":"Defined a redox-controlled transcriptional input, showing Glrx-dependent TRAF6 de-glutathionylation activates NF-κB to drive IL-33 transcription in macrophages.","evidence":"Glrx KO mice, TRAF6 glutathionylation assay and NF-κB ChIP-seq at the IL-33 promoter","pmids":["30682073"],"confidence":"Medium","gaps":["Single lab","Relative contribution vs other NF-κB stimuli unclear"]},{"year":2020,"claim":"Established IL-33 as an astrocyte-derived regulator of homeostatic synaptic plasticity acting on a neuronal receptor complex.","evidence":"Conditional KO, optogenetics, pharmacological ST2 blockade and behavioral memory assays in CA1","pmids":["33443211"],"confidence":"High","gaps":["Neuronal receptor complex composition not fully resolved here","Secretion mechanism not addressed"]},{"year":2020,"claim":"Identified a pathogen-derived trigger of IL-33 release, showing S. aureus Sbi drives keratinocyte IL-33 release TLR-independently.","evidence":"FPLC/MS identification, recombinant Sbi, bacterial mutants and IL-33 KO mice","pmids":["33011245"],"confidence":"Medium","gaps":["Host receptor for Sbi-driven release not identified"]},{"year":2021,"claim":"Mapped the chromatin-level transcriptional control of IL33, showing FAK kinase activity gates c-Jun binding to the Il33 enhancer.","evidence":"ATAC-seq, RNA-seq and c-Jun ChIP with FAK manipulation","pmids":["33420223"],"confidence":"Medium","gaps":["Single lab","Link between FAK and enhancer remodeling enzymes not defined"]},{"year":2021,"claim":"Connected an asthma risk variant to IL33 regulation via long-range chromatin looping and OCT-1 binding.","evidence":"3C, enhancer-blocking reporter assays and eQTL analysis in airway epithelial cells","pmids":["34675193"],"confidence":"Medium","gaps":["Direct OCT-1 causality not proven by perturbation","Single lab"]},{"year":2021,"claim":"Defined an upstream epithelial signaling axis (PI3K-Akt-GSK3β) that drives IL-33 expression and downstream IL-13-dependent secretory cell expansion.","evidence":"Conditional Sprouty2 KO, organoid pharmacological epistasis and IL-13 neutralization","pmids":["33547321"],"confidence":"Medium","gaps":["Direct transcriptional effector linking GSK3β to IL33 not identified"]},{"year":2022,"claim":"Identified thrombin as a maturation protease that cleaves IL-33 at R48/R106 to generate a potent ST2-activating form.","evidence":"In vitro cleavage with site identification and in vivo thrombin-inhibitor rescue of type 2 responses","pmids":["34995358"],"confidence":"Medium","gaps":["Physiological source of active thrombin at IL-33 sites unclear","Single lab"]},{"year":2022,"claim":"Established IL-33 as a developmental regulator of microglial synapse remodeling acting through enhancer/AP-1 remodeling and MARCO.","evidence":"CNS-specific IL-33 KO, ATAC-seq, MARCO KO, electrophysiology and EEG","pmids":["36520518"],"confidence":"High","gaps":["Whether IL-33 acts via ST2 on microglia not fully resolved","Supraphysiological dosing caveat"]},{"year":2022,"claim":"Showed cross-cytokine priming of the IL-33 axis, with IL11 inducing IL-33 and its receptor in fibroblasts via STAT3.","evidence":"RNA-seq and STAT3 vs MEK/ERK pharmacological inhibition in primary fibroblasts","pmids":["36012165"],"confidence":"Medium","gaps":["Functional consequence of primed axis not tested in vivo","Single lab"]},{"year":2023,"claim":"Identified P2Y13 as a purinergic gatekeeper controlling nuclear-to-cytoplasmic translocation and release of IL-33 upon allergen/virus exposure.","evidence":"P2Y13 KO and antagonists with IL-33 localization imaging in primary airway epithelium","pmids":["34860143"],"confidence":"Medium","gaps":["Molecular machinery of translocation downstream of P2Y13 not defined"]},{"year":2023,"claim":"Identified MDM2 as the E3 ligase ubiquitinating the IL-33 N-terminus, defining the counterpart to USP21 in stability control.","evidence":"Ubiquitination and proteasome assays with Co-IP plus PLP/Pdxk in vivo modulation","pmids":["37217797"],"confidence":"Medium","gaps":["Ubiquitin chain linkage not characterized","Single lab"]},{"year":2024,"claim":"Defined a receptor-switch mechanism, showing oxidized IL-33 abandons ST2 and instead signals through a RAGE/EGFR complex to drive airway remodeling.","evidence":"ALI epithelial models, scRNA-seq and antibody neutralization of RAGE/EGFR","pmids":["37442582"],"confidence":"Medium","gaps":["Direct RAGE/EGFR-IL-33ox binding not structurally resolved","Single lab"]},{"year":2024,"claim":"Identified the unconventional secretion route for IL-33, showing TMED10-dependent active secretion from astrocytes via the IL-1-like domain.","evidence":"Co-IP with domain mapping plus IL-33/ST2 conditional KO behavioral phenotyping","pmids":["38663774"],"confidence":"Medium","gaps":["Generality of TMED10 secretion beyond astrocytes untested","Single Co-IP for the interaction"]},{"year":2024,"claim":"Connected tumor-derived IL-33 to neutrophil effector function, showing secreted IL-33 induces NET formation via PADI4 through Akt/mTOR.","evidence":"IL-33 KO/knockdown in HCC cells, mTOR and PADI4 inhibitors and NET quantification in vivo","pmids":["39585643"],"confidence":"Medium","gaps":["Receptor mediating IL-33 effect on neutrophils not defined here","Single lab"]},{"year":null,"claim":"How the nuclear, secreted, oxidized, and cleaved states of IL-33 are coordinately switched in a single cell, and the relative in vivo contribution of ST2-dependent versus ST2-independent (RAGE/EGFR, nuclear) functions, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating localization, modification state, and receptor choice","Structural basis of chromatin binding and of the IL-33ox-RAGE/EGFR complex undefined","Tissue-specific dominance of competing pathways unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,5,17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,19]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,19,23]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,18,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,17,6,16]},{"term_id":"R-HSA-162582","term_label":"Signal 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Involved in the maturation of Th2 cells inducing the secretion of T-helper type 2-associated cytokines (PubMed:17853410, PubMed:18836528). Also involved in activation of mast cells, basophils, eosinophils and natural killer cells (PubMed:17853410, PubMed:18836528). Acts as an enhancer of polarization of alternatively activated macrophages (PubMed:19841166). Acts as a chemoattractant for Th2 cells, and may function as an 'alarmin', that amplifies immune responses during tissue injury (PubMed:17853410, PubMed:18836528). Induces rapid UCP2-dependent mitochondrial rewiring that attenuates the generation of reactive oxygen species and preserves the integrity of Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages (By similarity) In quiescent endothelia the uncleaved form is constitutively and abundantly expressed, and acts as a chromatin-associated nuclear factor with transcriptional repressor properties, it may sequester nuclear NF-kappaB/RELA, lowering expression of its targets (PubMed:21734074). This form is rapidely lost upon angiogenic or pro-inflammatory activation (PubMed:18787100)","subcellular_location":"Nucleus; Chromosome; Cytoplasm; Cytoplasmic vesicle, secretory vesicle; Secreted","url":"https://www.uniprot.org/uniprotkb/O95760/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL33","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL33","total_profiled":1310},"omim":[{"mim_id":"620492","title":"MEDIATOR COMPLEX SUBUNIT 31; MED31","url":"https://www.omim.org/entry/620492"},{"mim_id":"608678","title":"INTERLEUKIN 33; IL33","url":"https://www.omim.org/entry/608678"},{"mim_id":"605658","title":"INTERLEUKIN 25; IL25","url":"https://www.omim.org/entry/605658"},{"mim_id":"605103","title":"NEUROMEDIN U; NMU","url":"https://www.omim.org/entry/605103"},{"mim_id":"604672","title":"CD209 ANTIGEN; CD209","url":"https://www.omim.org/entry/604672"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"urinary bladder","ntpm":114.2}],"url":"https://www.proteinatlas.org/search/IL33"},"hgnc":{"alias_symbol":["DVS27","DKFZp586H0523","NF-HEV","IL1F11"],"prev_symbol":["C9orf26"]},"alphafold":{"accession":"O95760","domains":[{"cath_id":"-","chopping":"31-65_78-87","consensus_level":"medium","plddt":51.3438,"start":31,"end":87},{"cath_id":"2.80.10.50","chopping":"117-267","consensus_level":"high","plddt":85.28,"start":117,"end":267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95760","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95760-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95760-F1-predicted_aligned_error_v6.png","plddt_mean":66.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL33","jax_strain_url":"https://www.jax.org/strain/search?query=IL33"},"sequence":{"accession":"O95760","fasta_url":"https://rest.uniprot.org/uniprotkb/O95760.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95760/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95760"}},"corpus_meta":[{"pmid":"20081870","id":"PMC_20081870","title":"Disease-associated functions of IL-33: the new kid in the IL-1 family.","date":"2010","source":"Nature reviews. 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Structure-based mutagenesis and binding assays defined the molecular mechanism by which ST2 specifically recognizes IL-33, showing surface-charge complementarity is critical for ligand-binding specificity. Small-angle X-ray scattering revealed that ST2 possesses hinge flexibility between its D3 domain and D1D2 module, while IL-1RAcP is rigid in the unbound state. The solution architecture of the IL-33–ST2–IL-1RAcP ternary complex was also determined.\",\n      \"method\": \"X-ray crystallography, SAXS, structure-based mutagenesis, binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 3.27 Å combined with mutagenesis and SAXS in a single rigorous study\",\n      \"pmids\": [\"23980170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nuclear IL-33 binds chromatin with ~10-fold slower intranuclear mobility than IL-1α (measured by FRAP). Chromatin binding restricts IL-33 release upon necrosis (full-length IL-33 is more resistant to necrosis-induced release than truncated IL-33 lacking chromatin-binding activity). Upon release, IL-33 and histones form a high-molecular-weight complex that synergistically activates ST2-mediated signaling, indicating chromatin binding is a post-translational mechanism regulating IL-33 releasability and bioactivity.\",\n      \"method\": \"FRAP, overexpression in epithelial cells, necrosis-induced release assay, gel filtration/high-MW complex analysis, receptor signaling assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (FRAP, release kinetics, complex analysis, signaling) in a single rigorous study\",\n      \"pmids\": [\"30108214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP21, a ubiquitin-specific protease, interacts with IL-33 in the nucleus and deubiquitinates it, thereby maintaining IL-33 protein stability. Depletion of USP21 reduces IL-33 protein levels and diminishes IL-33-mediated NF-κB p65 promoter transcriptional activity, linking IL-33 ubiquitination to its nuclear function.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, proteasome assay, NF-κB reporter assay\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single Co-IP plus knockdown with functional readout, no structural validation\",\n      \"pmids\": [\"25197364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-33 activates core stem cell genes (NANOG, NOTCH3, OCT3/4) in colon cancer cells via the ST2 signaling pathway and induces phosphorylation and activation of JNK; activated c-Jun then binds the promoters of these stem cell genes. IL-33 also recruits macrophages into the tumor microenvironment and stimulates them to produce prostaglandin E2, which further supports cancer stemness.\",\n      \"method\": \"In vitro stimulation, Western blotting for p-JNK, chromatin immunoprecipitation (c-Jun on stem cell gene promoters), overexpression/administration in vivo tumor models, macrophage co-culture\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating c-Jun binding plus in vivo and in vitro functional studies in a single lab\",\n      \"pmids\": [\"28249897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-33 activates dendritic cells via an IL-33–ST2–MyD88–STAT1 signaling axis. MyD88 is required for IL-33-mediated increases in myeloid DC (mDC) number and upregulation of costimulatory molecules; ST2 and STAT1 cooperate with MyD88 to induce costimulatory molecule expression on mDCs in response to IL-33.\",\n      \"method\": \"In vivo rIL-33 administration, genetic knockout of MyD88/ST2/STAT1, flow cytometry, antigen cross-presentation assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic knockouts with defined cellular phenotype, single lab\",\n      \"pmids\": [\"28011934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A loss-of-function splice-site mutation in IL33 (rs146597587-C) produces a truncated IL-33 protein that has normal intracellular localization but neither binds the IL-33 receptor ST2 nor activates ST2-expressing cells, demonstrating that the C-terminal region (last 66 amino acids) is required for receptor binding and functional activity.\",\n      \"method\": \"Whole-genome sequencing, allele-specific RNA sequencing, recombinant truncated IL-33 protein binding assay, cell activation assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding and activation assays on recombinant truncated protein, replicated in population and molecular experiments\",\n      \"pmids\": [\"28273074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-33-deficient Treg cells show attenuated suppressive properties and facilitate tumor regression in an ST2-independent fashion. On activation, Il33-/- Treg cells exhibit epigenetic reprogramming with increased chromatin accessibility at the Ifng locus, leading to elevated IFN-γ production via an NF-κB–T-bet-dependent mechanism. IFN-γ ablation restores Il33-/- Treg cell suppressive properties, establishing IFN-γ as the effector of IL-33-dependent Treg stability.\",\n      \"method\": \"Genetic knockout (Il33-/- Tregs), ATAC-seq, in vivo tumor models, IFN-γ ablation rescue experiment\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ATAC-seq, genetic KO, epistasis rescue with IFN-γ ablation) in a single rigorous study\",\n      \"pmids\": [\"31844326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in hippocampal CA1. Neuronal activity blockade increases IL-33 expression and secretion by CA1 astrocytes; this IL-33 stimulates excitatory synapse formation and neurotransmission by activating the neuronal IL-33 receptor complex and promoting synaptic recruitment of PSD-95. Conditional knockout of IL-33 in CA1 astrocytes decreases excitatory synapse number, and blockade of IL-33/ST2 signaling impairs homeostatic plasticity and spatial memory.\",\n      \"method\": \"Conditional KO, optogenetic inhibition, tetrodotoxin slice experiments, in vivo rIL-33 administration, intracerebroventricular decoy receptor injection, behavioral memory assays, immunostaining for PSD-95\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KO, optogenetics, pharmacological blockade, behavioral assays) in a single rigorous study\",\n      \"pmids\": [\"33443211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-33 promotes microglial synapse remodeling during brain development. Supraphysiological IL-33 alters the microglial enhancer landscape and increases binding of AP-1/FOS transcription factors, inducing expression of the scavenger receptor MARCO. CNS-specific deletion of IL-33 leads to increased excitatory/inhibitory synaptic balance and absence-like epileptiform activity; MARCO-deficient mice recapitulate excess thalamic excitatory synapses, indicating MARCO as a downstream mediator of IL-33-driven synapse engulfment.\",\n      \"method\": \"CNS-specific IL-33 KO mice, ATAC-seq/enhancer landscape analysis, MARCO KO, single-cell electrophysiology, EEG, synapse counting\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with epigenomic profiling and functional electrophysiological readouts in a single rigorous study\",\n      \"pmids\": [\"36520518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Oxidized IL-33 (IL-33ox), a non-ST2-binding form, activates an ST2-independent pathway by forming a complex with RAGE and EGFR on airway epithelial cells. Activation of this RAGE/EGFR complex impairs epithelial wound closure and induces airway remodeling (increased mucus-producing cells, reduced epithelial defense functions) in vitro and in COPD ALI cultures.\",\n      \"method\": \"In vitro epithelial damage assays, 3D air-liquid interface models, bulk and single-cell RNA sequencing, antibody-based pathway neutralization\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex formation and functional consequences demonstrated in multiple in vitro models, single lab\",\n      \"pmids\": [\"37442582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Thrombin directly cleaves IL-33 at specific amino acid residues (R48 and R106) to generate a mature, biologically active form with potent ST2-stimulating activity. Low-molecular-weight heparin (indirect thrombin inhibitor) restrains papain- and fungus-induced type 2 immune responses by inhibiting IL-33 cleavage in vivo.\",\n      \"method\": \"In vitro cleavage assay (identification of cleavage sites R48/R106), in vivo mouse models with thrombin inhibitors, ELISA, ILC2 functional assays\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage assay with site identification plus in vivo rescue, single lab\",\n      \"pmids\": [\"34995358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MDM2 (an E3 ubiquitin ligase) ubiquitinates the N-terminus of IL-33 and sustains its stability in epithelial cells. PLP (active form of vitamin B6) reduces MDM2-mediated IL-33 polyubiquitination and decreases IL-33 levels through the proteasome pathway, thereby dampening type 2 immune responses.\",\n      \"method\": \"In vivo PLP/PL administration, Pdxk heterozygous mice, ubiquitination assay, proteasome inhibitor experiments, co-immunoprecipitation\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay identifying MDM2 as the E3 ligase combined with genetic and pharmacological in vivo evidence, single lab\",\n      \"pmids\": [\"37217797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Focal adhesion kinase (FAK) controls chromatin accessibility at the Il33 gene promoter/enhancer regions. FAK kinase activity is required for c-Jun (AP-1) binding to the Il33 enhancer, thereby regulating IL-33 gene expression. ATAC-seq integrated with RNA-seq demonstrated FAK-dependent chromatin accessibility linked to Il33 differential expression.\",\n      \"method\": \"ATAC-seq, RNA-seq, ChIP (c-Jun binding to Il33 enhancer), pharmacological/genetic FAK manipulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ATAC-seq and ChIP with FAK-dependent c-Jun binding to IL33 enhancer, single lab\",\n      \"pmids\": [\"33420223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sprouty2 loss in colonic epithelial cells activates PI3K/Akt signaling leading to GSK3β inhibition, which in turn drives epithelial IL-33 expression. Elevated epithelial IL-33 increases stromal IL-13+ cells in vivo; IL-13 then induces tuft and goblet cell expansion. This PI3K–Akt–GSK3β–IL-33–IL-13 axis links epithelial signaling to secretory cell differentiation.\",\n      \"method\": \"Conditional Sprouty2 KO, in vivo intestinal phenotyping, in vitro organoids with PI3K/Akt inhibitors, GSK3β inhibitor treatment, IL-13 neutralization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO combined with pharmacological epistasis and organoid experiments in a single lab\",\n      \"pmids\": [\"33547321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL11 stimulation of fibroblasts induces IL-33 expression (38-fold upregulation) in a STAT3-dependent (not MEK/ERK-dependent) manner, as demonstrated by pharmacological inhibition of STAT3 versus MEK/ERK. IL11 also upregulates IL1RL1 (the IL-33 receptor) 18-fold in the same cells, priming the IL-33 alarmin response.\",\n      \"method\": \"Primary human fibroblast culture, RNA sequencing, STAT3 and MEK/ERK pharmacological inhibitors, proteomics\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq and pathway inhibitors identifying STAT3 as the required signaling node, single lab\",\n      \"pmids\": [\"36012165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-33 activates mTORC1 in CD8+ T cells (evidenced by increased phospho-S6 ribosomal protein), leading to upregulation of Glut1 and glycolytic enzymes via mTORC1, and increased glucose uptake and lactate production (Warburg effect). mTORC1 inhibitors suppressed IL-33-induced CD8+ T cell activation. Extracellular (not nuclear) IL-33 contributed to CD8+ T cell activation in LCMV infection in vivo.\",\n      \"method\": \"Adoptive transfer of IL-33 KO vs. WT T cells, in vitro stimulation assays, phospho-S6 Western blot/flow cytometry, mTORC1 inhibitor treatment, glycolytic rate assay, glucose uptake measurement\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoprotein assays, pharmacological inhibition, and metabolic assays in a single lab\",\n      \"pmids\": [\"34411293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-33 promotes acute kidney injury (AKI) through CD4+ T cell-mediated production of CXCL1. Administration of soluble ST2 (decoy receptor) reduced CD4+ T cell infiltration, serum creatinine, ATN and apoptosis; conversely, recombinant IL-33 exacerbated AKI, and this exacerbation did not occur in CD4-deficient mice. CXCL1 receptor-deficient mice also showed attenuated AKI, placing the pathway as IL-33 → CD4 T cells → CXCL1 → renal injury.\",\n      \"method\": \"Soluble ST2 administration, recombinant IL-33 administration, CD4-deficient mice, CXCL1 receptor KO mice, serum creatinine, histopathology, cytokine ELISA\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis across multiple KO/deficient mouse strains with defined cellular phenotype, single lab\",\n      \"pmids\": [\"21949094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-33 exacerbates autoantibody-induced arthritis specifically through mast cells expressing ST2. Mast cell-deficient mice and ST2-/- mice failed to show IL-33-mediated disease exacerbation; reconstitution of ST2-/- recipients with WT mast cells (but not ST2-/- mast cells) restored IL-33-mediated exacerbation. IL-33 enhanced autoantibody-mediated mast cell degranulation in vitro and in synovial tissue in vivo.\",\n      \"method\": \"ST2-/- mice, mast cell-deficient mice, mast cell reconstitution experiments, in vitro mast cell degranulation assay, in vivo synovial tissue analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal reconstitution experiments with WT and ST2-/- mast cells, plus in vitro and in vivo validation\",\n      \"pmids\": [\"20139274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Active secretion of IL-33 from astrocytes occurs via an unconventional protein secretion pathway dependent on interaction with TMED10 (transmembrane emp24 domain 10). The IL-1-like cytokine domain of IL-33 mediates this interaction. IFN-γ promotes active secretion. Knockout of Il-33 or its receptor St2 induced hippocampal and spinal cord astrocyte activation and depressive-like behavior in naïve mice.\",\n      \"method\": \"Co-immunoprecipitation (IL-33 with TMED10), domain mapping, IL-33/ST2 conditional KO, behavioral assays, EAE model\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus multiple KO phenotypes, single lab\",\n      \"pmids\": [\"38663774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Epithelial nuclear IL-33 is upstream of IL-8 and IL-6 production in esophageal epithelial cells. IFN-γ induces nuclear IL-33 expression via a JAK/p38 MAPK/STAT1 pathway; IL-33 knockdown (siRNA) dampens IFN-γ- and deoxycholic acid-induced IL-8 and IL-6 production, establishing a non-cytokine, intranuclear regulatory function for IL-33 in esophageal inflammation.\",\n      \"method\": \"IL-33 siRNA knockdown, STAT1 siRNA, JAK and p38 MAPK inhibitors, cytokine ELISA, stratified epithelial culture model\",\n      \"journal\": \"Journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with pharmacological pathway dissection in an organotypic model, single lab\",\n      \"pmids\": [\"25129514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The asthma-associated SNP rs1888909 within an enhancer-blocking element at the IL33 locus is associated with IL33 gene expression in airway epithelial cells and IL-33 protein levels in plasma, potentially through differential binding of the transcription factor OCT-1 (POU2F1) to the risk allele. Chromatin conformation capture showed this 5 kb region loops to the IL33 promoter.\",\n      \"method\": \"3C (chromatin conformation capture), reporter assays (enhancer-blocking), eQTL analysis in airway epithelial cells, OCT-1 binding assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin looping (3C) and reporter assays with OCT-1 binding, single lab\",\n      \"pmids\": [\"34675193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Glutaredoxin-1 (Glrx) controls IL-33 production in macrophages by regulating de-glutathionylation of TRAF6, which is required for TRAF6 activation; this in turn activates IKKβ and NF-κB, which drives IL-33 transcription as a NF-κB-responsive gene. Glrx knockdown also impairs downstream IL-33-induced (exogenous, via ST2L) IL-33 mRNA induction.\",\n      \"method\": \"Glrx KO mice, siRNA knockdown in RAW264.7 cells, chromatin IP-seq (NF-κB binding at IL-33 promoter), TRAF6 glutathionylation assay, NF-κB inhibitors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq for NF-κB, TRAF6 glutathionylation assay, genetic KO, single lab\",\n      \"pmids\": [\"30682073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-33 expression in Multiple Sclerosis PBMCs is regulated by HDAC3: IL-33 expression is inhibited by the HDAC inhibitor Trichostatin A (TSA), while IL-1β expression is not, indicating specific epigenetic regulation of IL-33 by HDAC activity. LPS stimulation co-induces IL-33 and HDAC3 in RRMS patients.\",\n      \"method\": \"HDAC inhibitor (TSA) treatment of PBMCs, LPS stimulation, RT-PCR/protein quantification\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pharmacological inhibitor experiment without ChIP or direct HDAC3-IL33 interaction evidence, single lab\",\n      \"pmids\": [\"25215310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"P2Y13 receptor (a purinergic GPCR) acts as a gatekeeper of nuclear IL-33 release in airway epithelial cells. Aeroallergen or virus exposure induces extracellular ADP/ATP release, activating P2Y13-R, which drives nuclear-to-cytoplasmic translocation and subsequent extracellular release of IL-33. Genetic deletion or pharmacological antagonism of P2Y13-R ablates IL-33 translocation and release in response to allergens and rhinovirus.\",\n      \"method\": \"P2Y13-R knockout mice and pharmacological antagonists, allergen/virus exposure of primary AECs, immunohistochemistry for IL-33 localization, ELISA\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO combined with pharmacological antagonism and direct localization measurements, single lab\",\n      \"pmids\": [\"34860143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S. aureus second immunoglobulin-binding protein (Sbi) directly drives rapid IL-33 release from human keratinocytes independently of the Toll-like receptor pathway. Sbi was identified by FPLC fractionation and mass spectrometry, confirmed by recombinant expression and S. aureus Sbi mutant strains; IL-33 was essential for the in vivo immune response to S. aureus in eczema-prone mice.\",\n      \"method\": \"FPLC fractionation, mass spectrometry, recombinant Sbi expression, Sbi mutant bacteria, ex vivo skin explants, IL-33 KO mice\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification of Sbi, confirmed with recombinant protein and loss-of-function bacterial mutant, in vivo validation, single lab\",\n      \"pmids\": [\"33011245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lenvatinib increases NDUFA4L2 expression in HCC cells, which promotes IL-33 production and secretion. Secreted IL-33 triggers neutrophil extracellular trap (NET) formation by increasing PADI4 expression in neutrophils via the Akt/mTOR signaling pathway. IL-33 knockdown in HCC cells reduced NET formation in the tumor microenvironment.\",\n      \"method\": \"IL-33 KO/knockdown in tumor cells, NDUFA4L2 overexpression, mTOR inhibitor (rapamycin), PADI4 inhibitor (GSK484), NET quantification (CitH3, MPO-DNA), in vivo HCC mouse models\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and pharmacological epistasis with multiple functional readouts, single lab\",\n      \"pmids\": [\"39585643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-33 stimulation induces ICAM-1 expression on murine bone-marrow-derived mast cells at both mRNA and protein levels. This induction is dependent on NF-κB signaling: pre-treatment with an NF-κB inhibitor dramatically reduces ICAM-1 expression. IL-33-treated mast cells show increased cell adhesion to LFA-1-coated surfaces.\",\n      \"method\": \"BMMCs stimulation, siRNA knockdown of ICAM-1, NF-κB inhibitor, cell adhesion assay, in vivo intradermal IL-33 injection with histological analysis\",\n      \"journal\": \"Allergology international : official journal of the Japanese Society of Allergology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibitor combined with siRNA and in vivo validation, single lab\",\n      \"pmids\": [\"26666474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-33 facilitates colorectal cancer cell proliferation via ST2 receptor → NF-κB signaling → COX2 upregulation → PGE2 production. ST2 blockade, NF-κB inhibition (shP65), and COX2 selective inhibitor or PGE2 neutralizing antibody each abolished the IL-33 proliferation-promoting effect. ST2-negative sorted primary CRC cells did not respond to IL-33.\",\n      \"method\": \"ST2 blocking antibody, flow cytometry sorting of ST2+/- cells, NF-κB shRNA, COX2 inhibitor, PGE2 neutralizing antibody, colony formation and viability assays, in vivo IL-33 transgenic tumor growth\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitors and genetic tools placing IL-33 in a defined signaling pathway, single lab\",\n      \"pmids\": [\"30119635\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-33 is a dual-function nuclear alarmin cytokine that resides in the nucleus bound to chromatin (slowing its release upon necrosis), is actively secreted via an unconventional TMED10-dependent pathway in astrocytes, and—once in the extracellular space—binds its primary receptor ST2 (with IL-1RAcP as co-receptor, whose ternary complex structure is solved) to activate downstream MyD88–NF-κB, MAPK, and mTORC1–glycolytic signaling cascades in diverse immune and non-immune cells; its bioactivity is regulated post-translationally by ubiquitination (MDM2 as E3 ligase, USP21 as deubiquitinase), protease cleavage (thrombin at R48/R106 generates a mature form), oxidation (IL-33ox loses ST2 binding but engages a RAGE/EGFR complex), and epigenetic control of its transcription by FAK-dependent c-Jun/AP-1 chromatin accessibility and NF-κB via TRAF6/Glrx redox signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-33 is a dual-function nuclear alarmin cytokine that links cellular damage and tissue-resident signaling to inflammatory, immune, and neural programs by acting both as a chromatin-associated nuclear factor and as a secreted ligand for the receptor ST2 [#0, #1, #19]. In the nucleus IL-33 binds chromatin with markedly slower mobility than IL-1\\u03b1, a property that restrains its release upon necrosis and that, upon release, generates high-molecular-weight IL-33\\u2013histone complexes which synergistically activate ST2 signaling [#1]; nuclear IL-33 also functions cell-intrinsically, sitting upstream of IL-8/IL-6 production in epithelial cells and stabilizing the suppressive phenotype of regulatory T cells, where its loss reprograms chromatin accessibility at the Ifng locus to drive NF-\\u03baB\\u2013T-bet\\u2013dependent IFN-\\u03b3 [#19, #6]. Extracellularly, IL-33 engages ST2 with IL-1RAcP as co-receptor; the ternary complex architecture and the surface-charge complementarity governing ST2 recognition have been defined structurally, and the C-terminal IL-1-like domain is required for receptor binding and activity [#0, #5]. ST2 engagement activates MyD88-dependent NF-\\u03baB, MAPK/JNK, STAT1, and mTORC1\\u2013glycolytic cascades across diverse cells\\u2014dendritic cells, mast cells, CD8+ T cells, and tumor epithelium\\u2014driving costimulatory molecule expression, mast cell degranulation, glycolytic activation, and NF-\\u03baB\\u2013COX2\\u2013PGE2\\u2013dependent proliferation and cancer stemness [#4, #17, #15, #27, #3]. Release and bioactivity are tightly regulated post-translationally: thrombin cleaves IL-33 at R48/R106 to generate a potent mature form, oxidation produces a non-ST2-binding IL-33ox that instead signals through a RAGE/EGFR complex, and protein stability is set by competing MDM2-mediated ubiquitination and USP21-mediated deubiquitination [#10, #9, #11, #2]. IL33 transcription and release are themselves controlled by FAK-dependent c-Jun/AP-1 chromatin accessibility, TRAF6/Glrx redox-driven NF-\\u03baB signaling, purinergic P2Y13 gating, and unconventional TMED10-dependent secretion from astrocytes, where IL-33 governs synaptic plasticity and microglial synapse remodeling [#12, #21, #23, #18, #7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the structural basis by which IL-33 is recognized by its receptor, answering how ligand specificity and ternary signaling-complex assembly are achieved.\",\n      \"evidence\": \"X-ray crystallography, SAXS and structure-based mutagenesis of the IL-33\\u2013ST2 and IL-33\\u2013ST2\\u2013IL-1RAcP complexes\",\n      \"pmids\": [\"23980170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address how oxidation or proteolysis alters the receptor interface\", \"No structure of the chromatin-bound nuclear form\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved why full-length IL-33 is retained intracellularly, showing chromatin binding is a post-translational brake on release that also produces signaling-active IL-33\\u2013histone complexes.\",\n      \"evidence\": \"FRAP, necrosis-induced release assays and high-MW complex analysis in epithelial cells\",\n      \"pmids\": [\"30108214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-binding domain and target loci not mapped\", \"In vivo relevance of IL-33\\u2013histone complexes not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected the C-terminal region of IL-33 directly to receptor function through a natural loss-of-function variant.\",\n      \"evidence\": \"Whole-genome sequencing plus recombinant truncated-protein binding and activation assays\",\n      \"pmids\": [\"28273074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address nuclear functions of the truncated protein beyond localization\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a cell-type-specific effector mechanism, showing IL-33 exacerbates arthritis specifically via ST2-expressing mast cells.\",\n      \"evidence\": \"ST2-/- and mast-cell-deficient mice with reciprocal WT vs ST2-/- mast cell reconstitution\",\n      \"pmids\": [\"20139274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling within mast cells not dissected here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed IL-33 in a defined organ-injury cascade, showing it drives acute kidney injury through CD4 T-cell-derived CXCL1.\",\n      \"evidence\": \"Soluble ST2 decoy, recombinant IL-33, and CD4-deficient and CXCL1-receptor-KO mice\",\n      \"pmids\": [\"21949094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor target cell not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified opposing enzymatic control of IL-33 stability, establishing USP21 as a nuclear deubiquitinase that preserves IL-33 and its NF-\\u03baB-promoting activity.\",\n      \"evidence\": \"Co-IP, knockdown, proteasome and NF-\\u03baB reporter assays\",\n      \"pmids\": [\"25197364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Ubiquitin linkage type and E3 partner not defined here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a non-cytokine intranuclear function, with IFN-\\u03b3-induced nuclear IL-33 acting upstream of IL-8/IL-6 in epithelial inflammation.\",\n      \"evidence\": \"siRNA knockdown with JAK/p38/STAT1 pathway inhibitors in organotypic esophageal culture\",\n      \"pmids\": [\"25129514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of nuclear gene regulation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped the receptor-proximal signaling required for IL-33-driven dendritic cell activation.\",\n      \"evidence\": \"In vivo rIL-33 with MyD88, ST2 and STAT1 knockouts and flow cytometry\",\n      \"pmids\": [\"28011934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not separate direct vs indirect effects on DCs\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked ST2 signaling to transcriptional reprogramming, showing IL-33 drives cancer stemness via JNK/c-Jun activation of stem-cell genes.\",\n      \"evidence\": \"Western blot, ChIP for c-Jun on stem-cell promoters, in vivo tumor and macrophage co-culture models\",\n      \"pmids\": [\"28249897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct c-Jun-to-stemness causality not isolated from microenvironment effects\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a clinically actionable epigenetic regulator of IL-33, showing HDAC3-dependent expression in MS PBMCs.\",\n      \"evidence\": \"HDAC inhibitor treatment of PBMCs with RT-PCR readout\",\n      \"pmids\": [\"25215310\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pharmacological inhibitor without ChIP or direct HDAC3-IL33 interaction evidence\", \"Specificity over other HDACs untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a receptor-independent nuclear role of IL-33 in restraining Treg-derived IFN-\\u03b3 via chromatin accessibility at the Ifng locus.\",\n      \"evidence\": \"Il33-/- Treg ATAC-seq, in vivo tumor models and IFN-\\u03b3 ablation rescue\",\n      \"pmids\": [\"31844326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which nuclear IL-33 alters Ifng chromatin not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected IL-33 to metabolic rewiring, showing extracellular IL-33 drives mTORC1-dependent glycolysis in CD8+ T cells.\",\n      \"evidence\": \"Phospho-S6 assays, mTORC1 inhibitors and glycolytic/glucose-uptake measurements with IL-33 KO T cells\",\n      \"pmids\": [\"34411293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ST2 dependence of the metabolic effect not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a redox-controlled transcriptional input, showing Glrx-dependent TRAF6 de-glutathionylation activates NF-\\u03baB to drive IL-33 transcription in macrophages.\",\n      \"evidence\": \"Glrx KO mice, TRAF6 glutathionylation assay and NF-\\u03baB ChIP-seq at the IL-33 promoter\",\n      \"pmids\": [\"30682073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relative contribution vs other NF-\\u03baB stimuli unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established IL-33 as an astrocyte-derived regulator of homeostatic synaptic plasticity acting on a neuronal receptor complex.\",\n      \"evidence\": \"Conditional KO, optogenetics, pharmacological ST2 blockade and behavioral memory assays in CA1\",\n      \"pmids\": [\"33443211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal receptor complex composition not fully resolved here\", \"Secretion mechanism not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a pathogen-derived trigger of IL-33 release, showing S. aureus Sbi drives keratinocyte IL-33 release TLR-independently.\",\n      \"evidence\": \"FPLC/MS identification, recombinant Sbi, bacterial mutants and IL-33 KO mice\",\n      \"pmids\": [\"33011245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Host receptor for Sbi-driven release not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the chromatin-level transcriptional control of IL33, showing FAK kinase activity gates c-Jun binding to the Il33 enhancer.\",\n      \"evidence\": \"ATAC-seq, RNA-seq and c-Jun ChIP with FAK manipulation\",\n      \"pmids\": [\"33420223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Link between FAK and enhancer remodeling enzymes not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected an asthma risk variant to IL33 regulation via long-range chromatin looping and OCT-1 binding.\",\n      \"evidence\": \"3C, enhancer-blocking reporter assays and eQTL analysis in airway epithelial cells\",\n      \"pmids\": [\"34675193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct OCT-1 causality not proven by perturbation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an upstream epithelial signaling axis (PI3K-Akt-GSK3\\u03b2) that drives IL-33 expression and downstream IL-13-dependent secretory cell expansion.\",\n      \"evidence\": \"Conditional Sprouty2 KO, organoid pharmacological epistasis and IL-13 neutralization\",\n      \"pmids\": [\"33547321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional effector linking GSK3\\u03b2 to IL33 not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified thrombin as a maturation protease that cleaves IL-33 at R48/R106 to generate a potent ST2-activating form.\",\n      \"evidence\": \"In vitro cleavage with site identification and in vivo thrombin-inhibitor rescue of type 2 responses\",\n      \"pmids\": [\"34995358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological source of active thrombin at IL-33 sites unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established IL-33 as a developmental regulator of microglial synapse remodeling acting through enhancer/AP-1 remodeling and MARCO.\",\n      \"evidence\": \"CNS-specific IL-33 KO, ATAC-seq, MARCO KO, electrophysiology and EEG\",\n      \"pmids\": [\"36520518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-33 acts via ST2 on microglia not fully resolved\", \"Supraphysiological dosing caveat\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed cross-cytokine priming of the IL-33 axis, with IL11 inducing IL-33 and its receptor in fibroblasts via STAT3.\",\n      \"evidence\": \"RNA-seq and STAT3 vs MEK/ERK pharmacological inhibition in primary fibroblasts\",\n      \"pmids\": [\"36012165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of primed axis not tested in vivo\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified P2Y13 as a purinergic gatekeeper controlling nuclear-to-cytoplasmic translocation and release of IL-33 upon allergen/virus exposure.\",\n      \"evidence\": \"P2Y13 KO and antagonists with IL-33 localization imaging in primary airway epithelium\",\n      \"pmids\": [\"34860143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular machinery of translocation downstream of P2Y13 not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MDM2 as the E3 ligase ubiquitinating the IL-33 N-terminus, defining the counterpart to USP21 in stability control.\",\n      \"evidence\": \"Ubiquitination and proteasome assays with Co-IP plus PLP/Pdxk in vivo modulation\",\n      \"pmids\": [\"37217797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain linkage not characterized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a receptor-switch mechanism, showing oxidized IL-33 abandons ST2 and instead signals through a RAGE/EGFR complex to drive airway remodeling.\",\n      \"evidence\": \"ALI epithelial models, scRNA-seq and antibody neutralization of RAGE/EGFR\",\n      \"pmids\": [\"37442582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RAGE/EGFR-IL-33ox binding not structurally resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the unconventional secretion route for IL-33, showing TMED10-dependent active secretion from astrocytes via the IL-1-like domain.\",\n      \"evidence\": \"Co-IP with domain mapping plus IL-33/ST2 conditional KO behavioral phenotyping\",\n      \"pmids\": [\"38663774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of TMED10 secretion beyond astrocytes untested\", \"Single Co-IP for the interaction\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected tumor-derived IL-33 to neutrophil effector function, showing secreted IL-33 induces NET formation via PADI4 through Akt/mTOR.\",\n      \"evidence\": \"IL-33 KO/knockdown in HCC cells, mTOR and PADI4 inhibitors and NET quantification in vivo\",\n      \"pmids\": [\"39585643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating IL-33 effect on neutrophils not defined here\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the nuclear, secreted, oxidized, and cleaved states of IL-33 are coordinately switched in a single cell, and the relative in vivo contribution of ST2-dependent versus ST2-independent (RAGE/EGFR, nuclear) functions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating localization, modification state, and receptor choice\", \"Structural basis of chromatin binding and of the IL-33ox-RAGE/EGFR complex undefined\", \"Tissue-specific dominance of competing pathways unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 5, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 19]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 19, 23]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 18, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 17, 6, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 15, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 9, 27, 25]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 8, 12, 20]}\n    ],\n    \"complexes\": [\n      \"IL-33\\u2013ST2\\u2013IL-1RAcP ternary receptor complex\",\n      \"IL-33ox\\u2013RAGE\\u2013EGFR complex\"\n    ],\n    \"partners\": [\n      \"ST2/IL1RL1\",\n      \"IL1RAcP\",\n      \"USP21\",\n      \"MDM2\",\n      \"TMED10\",\n      \"RAGE\",\n      \"EGFR\",\n      \"MyD88\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}